Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer
A Phase I Clinical Trial Combining Nivolumab and Tumor Infiltrating Lymphocytes (TIL) for Patients With Advanced Non-Small Cell Lung Cancer
2 other identifiers
interventional
20
1 country
2
Brief Summary
Investigators plan to study the safety, side effects, and benefits of tumor-infiltrating lymphocytes (TILs) when they are given with the drug nivolumab. Nivolumab is a type of immunotherapy - a drug that is used to boost the ability of the immune system to fight cancer, infection, and other diseases.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_1 nonsmall-cell-lung-cancer
Started Oct 2017
Longer than P75 for phase_1 nonsmall-cell-lung-cancer
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
July 11, 2017
CompletedFirst Posted
Study publicly available on registry
July 12, 2017
CompletedStudy Start
First participant enrolled
October 11, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 13, 2021
CompletedResults Posted
Study results publicly available
April 13, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
June 9, 2023
CompletedJuly 24, 2023
July 1, 2023
3.3 years
July 11, 2017
January 4, 2022
July 18, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Rate of Dose Limiting Toxicity (DLT)
Investigators plan to demonstrate that treatment with nivolumab in patients undergoing TIL therapy is safe with a continuous Pocock-type stopping boundary for serious toxicity of \< 17%, with safety reported based upon Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. DLT defined as: any grade ≥3 immune-related adverse event definitely attributable to nivolumab. DLT related to adoptive cell therapy will be defined as a non-hematologic grade 4 or higher adverse event that is immediately life-threatening occurring upon or after the start of therapy that is immediately life-threatening and not related to non-small cell lung cancer or other pre-existing condition. Safety: Toxicity will be assessed within 4 weeks of the adoptive TIL transfer. The accrual will be halted if excessive numbers of participants with toxicity are seen. For example, if there are 5 or more out of 10 participants (full follow-up) with toxicity, the trial will be stopped.
Up to 40 months
Secondary Outcomes (1)
Number of Participants With Objective Response
Up to 40 months
Study Arms (1)
TIL+ Nivolumab
EXPERIMENTALTumor-infiltrating Lymphocyte Therapy (TIL) + Nivolumab Treatment Plan: Tumor harvest, Tumor-infiltrating Lymphocytes growth, 4 cycles of nivolumab, cytoreductive chemotherapy with cyclophosphamide and fludarabine, TIL infusion, Interleukin-2 treatment.
Interventions
Tumor harvest for TIL growth in the lab: A sample of the participant's tumor will be collected and sent to the lab for TIL growth. TIL will be prepared and cryopreserved.
Nivolumab will be administered intravenously at a fixed dose of 240 mg for 4 doses every 2 weeks prior to TIL. Nivolumab dose will be fixed at 480 mg every 4 weeks up to 12 months after TIL.
Cyclophosphamide will be administered at 60 mg/kg/day IV in 250 mL normal saline (NS) over approximately 2 hours. Cyclophosphamide will be initiated seven days prior to the anticipated TIL transfer, and the precise timing will depend on the rate of in vitro TIL growth. The dose will be based on the patient's body weight, but to prevent undue toxicity, it will not exceed a dose greater than 140% of the maximum ideal body weight per Metropolitan Life Insurance Company, Height and Weight Table.
After administration of Cyclophosphamide, Fludarabine will then be infused at 25 mg/m\^2 intravenous piggyback (IVPB) daily over approximately 30 minutes starting 5 days prior to TIL transfer. To prevent undue toxicity with fludarabine, the dose will be based on body surface area (BSA), but will not exceed a dose calculated on surface areas based on body weights greater than 140% of the maximum ideal body weight per Metropolitan Life Insurance Company Height and Weight Tables.
On day 0, all patients will receive TIL administered according to the current Moffitt Cell Therapy TIL Standard Operating Procedure (SOP). Eight (8) to twelve (12) hours after completing the TIL infusion, all participants will begin intermediate-dose decrescendo interleukin-2 (IL-2).
Interleukin-2 (IL-2) - a drug used to help the body's response to treatment on the immune system. A high dose regimen of IL-2 will be given after the infusion of the T-cells.
Eligibility Criteria
You may qualify if:
- Age \>18 years
- Able to understand and give written informed consent
- Confirmed or suspected diagnosis of stage IV or recurrent non-small cell lung cancer (NSCLC). For suspected NSCLC, diagnosis must be histologically or cytologically confirmed prior to start of nivolumab treatment. Neuroendocrine cancers, or mixed neuroendocrine features in \>10% of tumor cells, are excluded.
- Tumor deemed accessible by metastasectomy (TIL harvest) which expects to yield \>1.5 cm\^3 of resectable tumor amount.
- Measurable disease, even after resection of applicable lesion for TIL harvest. Defined as ≥1 lesion that is ≥10 mm in one dimension by CT scan, MRI, or calipers on clinical exam.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Expected survival \> 6 months
- Patients with activating Epidermal Growth Factor Receptor (EGFR) mutation or Anaplastic Lymphoma Kinase (ALK) rearrangement which is expected to be responsive to available tyrosine kinase inhibitor therapy, must have been previously treated with an applicable tyrosine kinase inhibitor.
- Adequate normal organ and marrow function in an assessment performed within 7 days (+ 3 day window) of enrollment, defined as: Hemoglobin ≥ 9.0 g/dL; Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9/L (\> 1000 per mm\^3); Platelet count ≥ 100 x 10\^9/L (\>100,000 per mm\^3); Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) ≤ 1.5x the institutional upper limit of normal (ULN), (This will not apply to patients with confirmed Factor XII deficiency.); Serum bilirubin ≤ 1.5x the institutional ULN, or ≤ 3x ULN if confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology); Aspartate Aminotransferase (AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5x institutional ULN unless liver metastases are present, in which case it must be ≤ 5x ULN; Serum creatinine of ≤ 1.5x institutional ULN; Albumin ≥ 2.5 g/dl.
- Positive screening Epstein Barr Virus (EBV) antibody titer on screening test.
- Cardiac stress test within past 6 months without evidence of reversible ischemia.
- Cardiac echocardiogram, stress test, or Multigated Acquisition Scan (MUGA) within past 6 months with demonstrated left ventricular ejection fraction (LVEF) \> 50%
- Pulmonary function tests within past 6 months showing Diffusion Lung Capacity for Carbon Monoxide (DLCO) \>50% of predicted. Adjusted DLCO based on hemoglobin concentration should be used, if available.
You may not qualify if:
- More than 5 lines of prior systemic therapy in the preceding 3 years.
- Any previous treatment with a PD-1 or PD-L1 inhibitor, including but not limited to: nivolumab, atezolizumab, pembrolizumab, or durvalumab.
- Current or prior use of any immunosuppressive medications, such as corticosteroids, within 14 days before enrollment. a.) Oral hydrocortisone, only for the purposes of a documented and confirmed adrenal insufficiency diagnosis, is permitted if ≤ 25 mg daily total dose. b.) Inhaled, intranasal, or topical corticosteroids are permitted.
- Patients with untreated brain metastases. Treated brain metastases with radiation or surgery are allowed if: ≤ 3 cm in size AND ≤ 4 in number AND there is no evidence of progressive disease, on brain imaging ≥ 28 days after last day of central nervous system (CNS) treatment.
- History of leptomeningeal metastases.
- Current or prior use of anticancer therapy before TIL collection: a.) Chemotherapy within the past 4 weeks; b.) Tyrosine kinase inhibitor (TKI) within the past 1 week; c.) Investigational therapy within the past 4 weeks or 4 half-lives, whichever is shorter.
- Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other than stable atrial fibrillation) and significant carotid artery stenosis.
- Known to be HIV positive, hepatitis B or C positive, or both Rapid Plasma Reagin (RPR) and Fluorescent Treponemal Antibody (FTA positive). (Hepatitis B surface or core antibody alone is not indicative of Hepatitis B Virus (HBV) infection).
- Patients with rapidly progressing tumors, as judged by the investigator.
- Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from electrocardiograms (ECGs) using Bazett's Correction
- Known history of previous tuberculosis
- Receipt of live attenuated vaccination within 30 days prior to first anticipated dose of nivolumab.
- History of allogeneic organ transplant
- History of primary immunodeficiency
- History of severe hypersensitivity to nivolumab, cyclophosphamide, fludarabine, interleukin-2, or any excipient
- +9 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- H. Lee Moffitt Cancer Center and Research Institutelead
- Bristol-Myers Squibbcollaborator
- Prometheus Inc.collaborator
- Stand Up To Cancercollaborator
- Iovance Biotherapeutics, Inc.collaborator
Study Sites (2)
University of Florida Health Cancer Center.
Gainesville, Florida, 32608, United States
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, 33612, United States
Related Publications (1)
Creelan BC, Wang C, Teer JK, Toloza EM, Yao J, Kim S, Landin AM, Mullinax JE, Saller JJ, Saltos AN, Noyes DR, Montoya LB, Curry W, Pilon-Thomas SA, Chiappori AA, Tanvetyanon T, Kaye FJ, Thompson ZJ, Yoder SJ, Fang B, Koomen JM, Sarnaik AA, Chen DT, Conejo-Garcia JR, Haura EB, Antonia SJ. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021 Aug;27(8):1410-1418. doi: 10.1038/s41591-021-01462-y. Epub 2021 Aug 12.
PMID: 34385708DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Ben Creelan, MD
- Organization
- Moffitt Cancer Center
Study Officials
- PRINCIPAL INVESTIGATOR
Ben Creelan, M.D.
H. Lee Moffitt Cancer Center and Research Institute
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- LTE60
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
July 11, 2017
First Posted
July 12, 2017
Study Start
October 11, 2017
Primary Completion
February 13, 2021
Study Completion
June 9, 2023
Last Updated
July 24, 2023
Results First Posted
April 13, 2022
Record last verified: 2023-07